Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10](=[O:13])[CH2:11][CH3:12])[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6][C:5]=1[NH:18]C(=O)C.S(=O)(=O)(O)O>CO.O.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10](=[O:13])[CH2:11][CH3:12])[C:7]([C:14]([F:16])([F:15])[F:17])=[CH:6][C:5]=1[NH2:18]
Reactant: CCC(=O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(=O)c1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 60 °C
Yield: 81.7 %

Procedure:
A solution of 2-acetylamino-5-propionyl-4-trifluoromethyl-benzoic acid methyl ester (260 mg, 0.82 mmol) in MeOH (2.6 mL) and water (0.54 mL) was treated with concentrated sulfuric acid (0.26 mL) and the mixture was heated to 60° C. for 1 h. It was then allowed to cool to r.t., and diluted with EtOAc. This mixture was washed once with aqueous sodium hydrogencarbonate (pH=8), once with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel 60, hexanes/EtOAc 100:0→80:20) to furnish 2-amino-5-propionyl-4-trifluoromethyl-benzoic acid methyl ester (185 mg, 0.67 mmol, 82%) as a white powder, m.p. 141-144° C., ESI-MS: m/z 276 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].C1OCCOCCOCCOCCOCCOC1.[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34]>O1CCCC1.CC(C)([O-])C.[K+]>[C:10]([CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:13])[F:1])[CH2:34][CH2:33][C:32]([O:36][CH3:37])=[O:35])#[N:11]
Reactant: N#CCc1ccccc1C(F)(F)F
Reactant: C=CC(=O)OC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCC(C#N)c1ccccc1C(F)(F)F
Reaction time: 0.67 h

Procedure:
2-(Trifluoromethyl)phenylacetonitrile (2.0 g) was dissolved in tetrahydrofuran (50 mL). Potassium tert-butoxide (60.6 mg), 18-crown-6 (2.85 g) and methyl acrylate (973 μL) were added at 0° C. and the mixture was stirred at the same temperature for 40 minutes. The reaction was terminated with saturated ammonium chloride, followed by dilution with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 30%) to obtain the title compound (2.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([OH:13])=O.[NH:14]1[CH2:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:14]1([C:11](=[O:13])[CH2:10][C:3]2[C:4]([F:9])=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)Cc1c(F)cc(O)cc1F
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1c(F)cc(O)cc1F)N1CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2,6-difluoro-4-hydroxyphenyl)acetic acid (0.98 g, 4.95 mmol) in 8 ml anhydrous DMF at RT was added azetidine (0.565 g, 9.89 mmol) and N,N-diisopropylethylamine (2.15 ml, 12.3 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.76 g, 9.89 mmol) was added to the solution and the reaction mixture was stirred at RT for 4 hrs. The solution was purified by preparative biotage Reverse phase (C-18) (50 g column), eluting with Acetonitrile/Water+0.1% formic acid (35% to 100%), to afford the title compound. LC/MS (m/z) 242.3 (M+15)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:23][CH3:24])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:25]1([N:22]([CH2:23][CH3:24])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)=[CH:42][CH:41]=3)[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCCC1
Temperature: 100 °C
Yield: 41.3 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclopentyl(ethyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.3 g, 0.653 mmol) and (4-(morpholinomethyl)phenyl)boronic acid (0.216 g, 0.98 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.249 g, 2.35 mmol) was added and solution purged with argon for 15 min. Then Pd (PPh3)4 (0.075 g, 0.065 mmol) was added and argon was purged again for 10 min. The reaction mixture was heated at 100° C. for 3 h. On completion, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.15 g, 41%). LCMS: 557.35 (M+1)+; HPLC: 99.13% (@254 nm) (Rt; 4.128; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.44 (s, 1H), 8.17 (t, 1H), 7.57 (d, 2H, J=8 Hz), 7.41 (s, 1H), 7.37 (d, 2H, J=8 Hz), 7.20 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.56-3.57 (m, 4H), 3.48 (s, 3H), 3.00-3.02 (m, 2H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.69-1.70 (m, 2H), 1.60 (m, 2H), 1.47-1.48 (m, 4H), 0.81 (t, 3H, J=6.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:20]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccc(F)cc2)c1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccc(F)cc1
Yield: 153.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.053 g (76%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [C:1]([C:4](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:5]([NH:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].C[NH:26][C:27](=[NH:29])[SH:28].S([O-])([O-])(=O)=O.[C:35]([O-])(=O)C.[Na+]>CN(C=O)C>[Cl:24][C:20]1[CH:19]=[C:18]([C:17]2[C:4]([C:5]([NH:7][CH2:8][CH:9]=[CH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:6])=[C:1]([CH3:2])[N:29]=[C:27]([S:28][CH3:35])[N:26]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)C(=Cc1cccc(Cl)c1)C(=O)NCC=Cc1ccccc1
Reactant: CC(=O)[O-]
Reactant: CNC(=N)S
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(C)c(C(=O)NCC=Cc2ccccc2)c(-c2cccc(Cl)c2)n1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
413 mg (1.21 mmol) of 2-acetyl-3-(3-chlorophenyl)-N-(3-phenyl-2-propen-1-yl) acrylamide was dissolved in 10 ml of DMF. 269 mg (0.968 mmol) of methylisothiourea-sulfate and 149 mg of (1.82 mmol) of sodium acetate were added thereto at room temperature and stirred at 100° C. for 2 days. DMF was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](=[O:14])([O-])[O-].[Na+].[Na+].[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[CH3:2][N:6]1[C@H:5]2[C@@:17]([CH3:21])([C:17]3[CH:21]=[CH:9][C:8]([C:2]4[S:3][C:4]5[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=5[N:6]=4)=[CH:7][C:18]=3[CH2:19][CH2:4]2)[CH2:18][CH2:19][C:11]1=[O:14]
Reactant: Clc1nc2ccccc2s1
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4nc5ccccc5s4)cc3CC[C@@H]12
Yield: 45 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2-chlorobenzothiazole (110 mg, 0.65 mmol), 0.65 mL of aqueous 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 18 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 107 mg (45%) of the title compound as an amorphous solid. mp 207°-212°. FDMS: m/e=362. α[D]589 =+88.83 (c=0.60, chloroform).
Reaction SMILES: [CH3:1][CH:2]([C:7](=O)[CH2:8][O:9][CH3:10])[C:3](OC)=[O:4].C(O)(=O)C.[CH:16]([NH2:18])=[NH:17].C[O-].[Na+]>CO>[CH3:1][C:2]1[C:3]([OH:4])=[N:17][CH:16]=[N:18][C:7]=1[CH2:8][O:9][CH3:10]
Reactant: COCC(=O)C(C)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCc1ncnc(O)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of methyl 2-methyl-4-(methyloxy)-3-oxobutanoate (Intermediate 47, 1.01 g, 6.31 mmol) in methanol (7 mL) was added formamidine acetate (0.722 g, 6.94 mmol) and 25% sodium methoxide in MeOH (3.0 mL, 6.31 mmol) and the resulting mixture was heated under reflux for 2 hours, cooled to room temperature and left to stand overnight. The reaction mixture was evaporated under reduced pressure. The residue was diluted with water, adjusted to pH 7 using aqueous 2M HCl solution and extracted with chloroform (×3). The chloroform layers were combined, dried under magnesium sulfate and evaporated under reduced pressure to give the title compound as a white solid (597 mg);
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:19]1([CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)Cl)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][N:7]([CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: Clc1ccc2c(n1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ccc2c(n1)CCN(C(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.9 %

Procedure:
To a solution of the product of step (c) (1.78 g, 0.1 mol) and triethylamine (2.21 ml, 0.016 mol) in CH2Cl2 (20 ml) was added diphenylchloromethane (2.13 ml, 0.012 mol). The reaction mixture was stirred at room temperature for 20 h and evaporated under reduced pressure. The residue was dissolved in DMA (20 ml) and heated to 100° C. for 18 h and once cooled, the solution was diluted with CH2Cl2 and washed sequentially with saturated aqueous sodium bicarbonate solution, H2O and saturated brine then dried over MgSO4. Evaporation under reduced pressure afforded the subtitle compound as a solid (1.0 g, 30%), Rf 0.7 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 335 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:17]S(C(C)(C)C)=O)[C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl>CO.O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH2:17])[C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(CC(NS(=O)C(C)(C)C)c2cnn(C)c2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(C)cc(CC(N)c2cnn(C)c2)c1
Yield: 77 %

Procedure:
A solution of RS 2-methyl-propane-2-sulfinic acid [2-(3,5-dimethyl-phenyl)-1-(1-methyl-1H-pyrazol-4-yl)-ethyl]-amide (2.0 g) in methanol (12 ml) was treated with a solution of hydrogenchloride in dioxane (12 ml, 4 N) at room temperature overnight. The reaction mixture was quenched with aqueous potassium carbonate solution and adjusted to pH 8-9, extracted and the organic phases dried over magnesium sulfate. After evaporation of the solvent a yellowish oil was obtained in 77% yield (1.05 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]4[C:41]([N+:42]([O-])=O)=[CH:40][CH:39]=[CH:38][C:37]=4[Cl:45])[CH2:32][CH2:31]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]4[C:37]([Cl:45])=[CH:38][CH:39]=[CH:40][C:41]=4[NH2:42])[CH2:32][CH2:31]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3[N+](=O)[O-])CC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(N)cccc3Cl)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 360 mg (0.56 mmol) of 1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester in 4 mL of MeOH was treated with 182 mg (5 eq) of zinc dust and glacial acetic acid (1.57 mL, 50 eq) at 25° C. The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a thick oil. The residue was taken up in CH2Cl2 (50 mL) and sat. NaHCO3 (20 mL). The organic layer was separated, washed with H2O (2×10 mL), dried over Na2SO4, and concentrated to afford 1-{3-[4-(2-amino-6-chloro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): exact mass calculated for C31H38ClF3N6O2, 618.27; m/z found, 619.3 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]([Cl:15])=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)=[O:7].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]([Cl:15])=[C:10]([CH2:14][Br:16])[CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(=O)c2cccs2)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1cccs1)c1cccc(CBr)c1Cl

Procedure:
A mixture of 11.8 parts of 2-chloro-m-tolyl 2-thienyl ketone, 8.9 parts of N-bromosuccinimide, 100 parts of carbon tetrachloride and 0.25 parts of benzoyl peroxide is stirred and refluxed for 2 hours. The precipitated succinimide if filtered off and washed on the filter which carbon tetrachloride. The filtrate is dried and evaporated, yielding α-bromo-2-chloro-m-tolyl 2-thienyl ketone as a residue.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[NH:15][C:14](=[S:16])[NH:13][C:12]2=[O:17])=[CH:2]1.[CH3:18]I>[OH-].[Na+].CO>[CH3:18][S:16][C:14]1[NH:13][C:12](=[O:17])[C:11](=[CH:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[N:15]=1
Reactant: O=C1NC(=S)NC1=Cc1c[nH]c2ncccc12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSC1=NC(=Cc2c[nH]c3ncccc23)C(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a solution of 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-2-thioxoimidazolidin-4-one (8 g, 32.8 mmol) in 12.6% aq. NaOH (12 mL) and methanol (80 mL), methyl iodide (2.25 mL, 36 mmol) was added and the reaction mixture stirred at RT for 4 h. Most of the solvent was distilled out and the precipitate was filtered and washed first with water, then with diethylether. The washings were concentrated and extracted with dichloromethane, dried over sodium sulphate and joined to the first solid crop. The whole crop was suspended in methanol, stirred 30′, filtered and dried to yield 2-(methylthio)-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-3,5-dihydro-4H-imidazol-4-one as a yellow solid (8.15 g, 31.6 mmol, 96%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([C@@H:43]2[CH2:47][CH2:46][O:45][CH2:44]2)[C:39](=[O:48])[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([C@@H:43]4[CH2:47][CH2:46][O:45][CH2:44]4)[C:39](=[O:48])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=c1cc(Br)ccn1[C@@H]1CCOC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccn([C@@H]3CCOC3)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 65 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 4-bromo-1-[(R)-tetrahydro-furan-3-yl]-1H-pyridin-2-one following a procedure analogous to that described in Example 1. Yield: 65% of theory; LC (method 3): tR=2.95 min; Mass spectrum (ESI+): m/z=517 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3cnn(C)c3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: Cn1cc(-c2cc3c(O)c(C(=O)NCCC(=O)O)ncc3n(Cc3ccccc3)c2=O)cn1
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (44 mg, 0.11 mmol), β-alanine (804 mg, 9.0 mmol) and NaOMe solution (13 mL, 6.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 4. The organic layer was dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 31 mg of the title compound as a yellow solid. MS: (+) m/z 448.29 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]([C:14]#[N:15])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:23]C)[CH:10]=3)[C:5]2=[O:25])[CH2:3][CH2:2]1.[C-]#N.[Na+].Cl>CS(C)=O.O>[CH:1]1([N:4]2[C:13]([C:14]#[N:15])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:23])[CH:10]=3)[C:5]2=[O:25])[CH2:2][CH2:3]1
Reactant: COc1ccc2c(=O)n(C3CC3)c(C#N)c(-c3cccc(F)c3)c2c1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1c(-c2cccc(F)c2)c2cc(O)ccc2c(=O)n1C1CC1
Temperature: 160 °C

Procedure:
A mixture of the methyl ether 61 (3 g, 9 mmol) and NaCN (3.5 g, 72 mmol) in DMSO was heated at 160° C. for 3 h. The mixture was cooled, diluted with water, acidified with concentrated HCl and then extracted with EtOAc. The combined organic extracts were basified with 1N NaOH and washed with EtOAc. The aqueous layer was acidified with concentrated HCl and then extracted with EtOAc. Drying with Na2SO4 and concentration in vacuo gave a residue was purified by crystallization from EtOAc/hexanes.
Reaction SMILES: C(O[C:6](=[O:25])[NH:7][C@@H:8]([CH2:21][CH:22]([CH3:24])[CH3:23])[C@@H:9]([OH:20])[CH2:10][C@H:11]([C:13](=[O:19])[NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:12])(C)(C)C.[Cl:26][C:27]1[CH:44]=[CH:43][C:30]2[C:31](C(O)=O)=[CH:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[O:35][C:29]=2[CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>Cl.O1CCOCC1.C(Cl)Cl>[CH2:15]([NH:14][C:13]([C@H:11]([CH3:12])[CH2:10][C@H:9]([OH:20])[C@@H:8]([NH:7][C:6]([C:31]1[C:30]2[CH:43]=[CH:44][C:27]([Cl:26])=[CH:28][C:29]=2[O:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[CH:32]=1)=[O:25])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)C1=Cc2ccccc2Oc2cc(Cl)ccc21
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)C)NC(=O)C1=Cc2ccccc2Oc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
((1S,2S,4R)-4-Butylcarbamoyl-2-hydroxy-1-isobutyl-pentyl)-carbamic acid tert-butyl ester (66 mg, 0.18 mmol) are dissolved in 4N HCl in dioxane (3 ml). After stirring for 1 h at rt the solvent is evaporated and the residue dried in vacuum. The residue is dissolved in DCM (3 ml) and 7-Chloro-dibenzo[b,f]oxepine-10-carboxylic acid (60 mg, 0.22 mmol, 1.2 eq), HOBT (30 mg, 0.22 mmol, 1.2 eq), EDCl (53 mg, 0.28 mmol, 1.5 eq) and triethylamine (0.077 ml, 0.55 mmol, 3 eq) are added. The mixture is stirred over night at rt. The reaction mixture is diluted with DCM and washed with water, bicarbonate and brine. The organic layer is dried over magnesium sulfate and the solvent is evaporated. Purification on silica (Flashmaster, DCM/methanol 100%→90%) and crystallization from DCM/hexane gives the products as white crystals (50 mg).